tbuckley/cabot-search huggingface dataset:
Unique functional responses differentially map onto genetic subtypes of dopamine neurons
Authors: Maite Azcorra, Zachary Gaertner, Connor Davidson, Qianzi He, Hailey Kim, Shivathmihai Nagappan, Cooper K Hayes, Charu Ramakrishnan, Lief Fenno, Yoon Seok Kim, Karl Deisseroth, Richard Longnecker, Rajeshwar Awatramani, Daniel A Dombeck
Journal: Nature Neuroscience (2023)

Abstract Dopamine neurons are characterized by their response to unexpected rewards, but they also fire during movement and aversive stimuli. Dopamine neuron diversity has been observed based on molecular expression profiles; however, whether different functions map onto such genetic subtypes remains unclear. In this study, we established that three genetic dopamine neuron subtypes within the substantia nigra pars compacta, characterized by the expression of Slc17a6 ( Vglut2 ), Calb1 and Anxa1 , each have a unique set of responses to rewards, aversive stimuli and accelerations and decelerations, and these signaling patterns are highly correlated between somas and axons within subtypes. Remarkably, reward responses were almost entirely absent in the Anxa1 + subtype, which instead displayed acceleration-correlated signaling. Our findings establish a connection between functional and genetic dopamine neuron subtypes and demonstrate that molecular expression patterns can serve as a common framework to dissect dopaminergic functions.
Fleaborne Typhus–Associated Deaths — Los Angeles County, California, 2022
Authors: Jemma Alarcón, Armine Sanosyan, Zuelma A. Contreras, Van P. Ngo, Ann Carpenter, Jill K. Hacker, William S. Probert, Dawn Terashita, Sharon Balter, Umme-Aiman Halai
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

Fleaborne typhus (also known as murine typhus), a widely distributed vectorborne zoonosis caused by Rickettsia typhi, is a moderately severe, but infrequently fatal illness; among patients who receive doxycycline, the case-fatality rate is <1%. Fleaborne typhus is a mandated reportable condition in California. Reported fleaborne typhus cases in Los Angeles County have been increasing since 2010, with the highest number (171) reported during 2022. During June-October 2022, Los Angeles County Department of Public Health learned of three fleaborne typhus-associated deaths. This report describes the clinical presentation, illness course, and methods used to diagnose fleaborne typhus in these three cases. Severe fleaborne typhus manifestations among these cases included hemophagocytic lymphohistiocytosis, a rare immune hyperactivation syndrome that can occur in the infection setting; myocarditis; and septic shock with disseminated intravascular coagulation. Increased health care provider and public health awareness of the prevalence and severity of fleaborne typhus and of the importance of early doxycycline therapy is essential for prevention and treatment efforts.
Methionine restriction-induced sulfur deficiency impairs antitumour immunity partially through gut microbiota
Authors: Ming Ji, Xiaojiang Xu, Qing Xu, Yun-Chung Hsiao, Cody Martin, Svetlana Ukraintseva, Vladimir Popov, Konstantin G Arbeev, Tom A Randall, Xiaoyue Wu, Liz M Garcia-Peterson, Juan Liu, Xin Xu, M Andrea Azcarate-Peril, Yisong Wan, Anatoliy I Yashin, Karthik Anantharaman, Kun Lu, Jian-Liang Li, Igor Shats, Xiaoling Li
Journal: Nature Metabolism (2023)

Abstract Restriction of methionine (MR), a sulfur-containing essential amino acid, has been reported to repress cancer growth and improve therapeutic responses in several preclinical settings. However, how MR impacts cancer progression in the context of the intact immune system is unknown. Here we report that while inhibiting cancer growth in immunocompromised mice, MR reduces T cell abundance, exacerbates tumour growth and impairs tumour response to immunotherapy in immunocompetent male and female mice. Mechanistically, MR reduces microbial production of hydrogen sulfide, which is critical for immune cell survival/activation. Dietary supplementation of a hydrogen sulfide donor or a precursor, or methionine, stimulates antitumour immunity and suppresses tumour progression. Our findings reveal an unexpected negative interaction between MR, sulfur deficiency and antitumour immunity and further uncover a vital role of gut microbiota in mediating this interaction. Our study suggests that any possible anticancer benefits of MR require careful consideration of both the microbiota and the immune system.
Early clonal extinction in glioblastoma progression revealed by genetic barcoding
Authors: Davide Ceresa, Francesco Alessandrini, Sara Lucchini, Daniela Marubbi, Francesca Piaggio, Jorge Miguel Mena Vera, Isabella Ceccherini, Daniele Reverberi, Irene Appolloni, Paolo Malatesta
Journal: Cancer Cell (2023)

Glioblastoma progression in its early stages remains poorly understood. Here, we transfer PDGFB and genetic barcodes in mouse brain to initiate gliomagenesis and enable direct tracing of glioblastoma evolution from its earliest possible stage. Unexpectedly, we observe a high incidence of clonal extinction events and progressive divergence in clonal sizes, even after the acquisition of malignant phenotype. Computational modeling suggests these dynamics result from clonal-based cell-cell competition. Through bulk and single-cell transcriptome analyses, coupled with lineage tracing, we reveal that Myc transcriptional targets have the strongest correlation with clonal size imbalances. Moreover, we show that the downregulation of Myc expression is sufficient to drive competitive dynamics in intracranially transplanted gliomas. Our findings provide insights into glioblastoma evolution that are inaccessible using conventional retrospective approaches, highlighting the potential of combining clonal tracing and transcriptomic analyses in this field.
Saliva antiviral antibody levels are detectable but correlate poorly with serum antibody levels following SARS-CoV-2 infection and/or vaccination
Authors: Siân E. Faustini, Alex Cook, Harriet Hill, Saly Al-Taei, Jennifer Heaney, Elena Efstathiou, Chloe Tanner, Neal Townsend, Zahra Ahmed, Mohammad Dinally, Madeeha Hoque, Margaret Goodall, Zania Stamataki, Timothy Plant, Iain Chapple, Adam F. Cunningham, Mark T. Drayson, Adrian M. Shields, Alex G. Richter
Journal: Journal of Infection (2023)

The importance of salivary SARS-CoV-2 antibodies, following infection and vaccination, has not been fully established. 875 healthcare workers were sampled during the first wave in 2020 and 66 longitudinally in response to Pfizer BioNTech 162b2 vaccination. We measured SARS-CoV-2 total IgGAM and individual IgG, IgA and IgM antibodies. IgGAM seroprevalence was 39.9%; however, only 34.1% of seropositive individuals also had salivary antibodies. Infection generated serum IgG antibodies in 51.4% and IgA antibodies in 34.1% of individuals. In contrast, the salivary antibody responses were dominated by IgA (30.9% and 12% generating IgA and IgG antibodies, respectively). Post 2nd vaccination dose, in serum, 100% of infection naïve individuals had IgG and 82.8% had IgA responses; in saliva, 65.5% exhibited IgG and 55.2% IgA antibodies. Prior infection enhanced the vaccine antibody response in serum but no such difference was observed in saliva. Strong neutralisation responses were seen for serum 6 months post 2nd-vaccination dose (median 87.1%) compared to low neutralisation responses in saliva (median 1%). Intramuscular vaccination induces significant serum antibodies and to a lesser extent, salivary antibodies; however, salivary antibodies are typically non-neutralising. This study provides further evidence for the need of mucosal vaccines to elicit nasopharyngeal/oral protection. Although saliva is an attractive non-invasive sero-surveillance tool, due to distinct differences between systemic and oral antibody responses, it cannot be used as a proxy for serum antibody measurement.
Mammalian SWI/SNF chromatin remodeling complexes promote tyrosine kinase inhibitor resistance in EGFR-mutant lung cancer
Authors: Fernando J. de Miguel, Claudia Gentile, William W. Feng, Shannon J. Silva, Akshay Sankar, Francisco Exposito, Wesley L. Cai, Mary Ann Melnick, Camila Robles-Oteiza, Madeline M. Hinkley, Jeanelle A. Tsai, Antja-Voy Hartley, Jin Wei, Anna Wurtz, Fangyong Li, Maria I. Toki, David L. Rimm, Robert Homer, Craig B. Wilen, Andrew Z. Xiao, Jun Qi, Qin Yan, Don X. Nguyen, Pasi A. Jänne, Cigall Kadoch, Katerina A. Politi
Journal: Cancer Cell (2023)

Acquired resistance to tyrosine kinase inhibitors (TKI), such as osimertinib used to treat EGFR-mutant lung adenocarcinomas, limits long-term efficacy and is frequently caused by non-genetic mechanisms. Here, we define the chromatin accessibility and gene regulatory signatures of osimertinib sensitive and resistant EGFR-mutant cell and patient-derived models and uncover a role for mammalian SWI/SNF chromatin remodeling complexes in TKI resistance. By profiling mSWI/SNF genome-wide localization, we identify both shared and cancer cell line-specific gene targets underlying the resistant state. Importantly, genetic and pharmacologic disruption of the SMARCA4/SMARCA2 mSWI/SNF ATPases re-sensitizes a subset of resistant models to osimertinib via inhibition of mSWI/SNF-mediated regulation of cellular programs governing cell proliferation, epithelial-to-mesenchymal transition, epithelial cell differentiation, and NRF2 signaling. These data highlight the role of mSWI/SNF complexes in supporting TKI resistance and suggest potential utility of mSWI/SNF inhibitors in TKI-resistant lung cancers.
A syntelog-based pan-genome provides insights into rice domestication and de-domestication
Authors: Dongya Wu, Lingjuan Xie, Yanqing Sun, Yujie Huang, Lei Jia, Chenfeng Dong, Enhui Shen, Chu-Yu Ye, Qian Qian, Longjiang Fan
Journal: Genome biology (2023)

Abstract Background Asian rice is one of the world’s most widely cultivated crops. Large-scale resequencing analyses have been undertaken to explore the domestication and de-domestication genomic history of Asian rice, but the evolution of rice is still under debate. Results Here, we construct a syntelog-based rice pan-genome by integrating and merging 74 high-accuracy genomes based on long-read sequencing, encompassing all ecotypes and taxa of Oryza sativa and Oryza rufipogon . Analyses of syntelog groups illustrate subspecies divergence in gene presence-and-absence and haplotype composition and identify massive genomic regions putatively introgressed from ancient Geng/ japonica to ancient Xian/ indica or its wild ancestor, including almost all well-known domestication genes and a 4.5-Mbp centromere-spanning block, supporting a single domestication event in main rice subspecies. Genomic comparisons between weedy and cultivated rice highlight the contribution from wild introgression to the emergence of de-domestication syndromes in weedy rice. Conclusions This work highlights the significance of inter-taxa introgression in shaping diversification and divergence in rice evolution and provides an exploratory attempt by utilizing the advantages of pan-genomes in evolutionary studies.
Neddylation of phosphoenolpyruvate carboxykinase 1 controls glucose metabolism
Authors: María J. Gonzalez-Rellan, Uxía Fernández, Tamara Parracho, Eva Novoa, Marcos F. Fondevila, Natalia da Silva Lima, Lucía Ramos, Amaia Rodríguez, Marina Serrano-Maciá, Gonzalo Perez-Mejias, Pilar Chantada-Vazquez, Cristina Riobello, Christelle Veyrat-Durebex, Sulay Tovar, Roberto Coppari, Ashwin Woodhoo, Markus Schwaninger, Vincent Prevot, Teresa C. Delgado, Miguel Lopez, Antonio Diaz-Quintana, Carlos Dieguez, Diana Guallar, Gema Frühbeck, Irene Diaz-Moreno, Susana B. Bravo, Maria L. Martinez-Chantar, Ruben Nogueiras
Journal: Cell Metabolism (2023)

Neddylation is a post-translational mechanism that adds a ubiquitin-like protein, namely neural precursor cell expressed developmentally downregulated protein 8 (NEDD8). Here, we show that neddylation in mouse liver is modulated by nutrient availability. Inhibition of neddylation in mouse liver reduces gluconeogenic capacity and the hyperglycemic actions of counter-regulatory hormones. Furthermore, people with type 2 diabetes display elevated hepatic neddylation levels. Mechanistically, fasting or caloric restriction of mice leads to neddylation of phosphoenolpyruvate carboxykinase 1 (PCK1) at three lysine residues—K278, K342, and K387. We find that mutating the three PCK1 lysines that are neddylated reduces their gluconeogenic activity rate. Molecular dynamics simulations show that neddylation of PCK1 could re-position two loops surrounding the catalytic center into an open configuration, rendering the catalytic center more accessible. Our study reveals that neddylation of PCK1 provides a finely tuned mechanism of controlling glucose metabolism by linking whole nutrient availability to metabolic homeostasis.
Bispecific antibodies targeting BCMA, GPRC5D, and FcRH5 for multiple myeloma therapy: latest updates from ASCO 2023 Annual Meeting
Authors: Juanjuan Zhao, Quan Ren, Xinyuan Liu, Xiangqian Guo, Yongping Song
Journal: Journal of Hematology & Oncology (2023)

Several bispecific antibodies (bsAbs) targeting BCMA, GPRC5D, and FcRH5 are in clinical trials for heavily pretreated multiple myeloma (MM) patients. Teclistamab was approved for relapsed/refractory MM therapy in 2022, while elranatamab, linvoseltamab, F182112, talquetamab, and cevostamab are currently undergoing clinical trials. This study summarizes several latest reports on bsAbs for the treatment of MM from the ASCO 2023 Annual Meeting.
CAR T cell therapies for diffuse midline glioma
Authors: Bryce C. Thomas, Dilana E. Staudt, Alicia M. Douglas, Michelle Monje, Nicholas A. Vitanza, Matthew D. Dun
Journal: Trends in cancer (2023)

Diffuse midline glioma (DMG) is a fatal pediatric cancer of the central nervous system (CNS). The location and infiltrative nature of DMG prevents surgical resection and the benefits of palliative radiotherapy are temporary; median overall survival (OS) is 9-11 months. The tumor immune microenvironment (TIME) is 'cold', and has a dominant immunosuppressive myeloid compartment with low levels of infiltrating lymphocytes and proinflammatory molecules. Because survival statistics have been stagnant for many decades, and therapies targeting the unique biology of DMG are urgently needed, this has prompted the clinical assessment of chimeric antigen receptor (CAR) T cell therapies in this setting. We highlight the current landscape of CAR T cell therapy for DMG, the role the TIME may play in the response, and strategies to overcome treatment obstacles.
From small to big, using microRNA profiling to investigate infant origins of childhood asthma
Authors: Weston T. Powell, Stephen R. Reeves
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Differential microRNA expression occurs in early respiratory viral infection and may be important for asthma pathogenesis. Further work to tie patterns of microRNA expression to clinical phenotypes is needed to inform future diagnostic tools and therapies.</b>https://bit.ly/3JZleLj
Long-term therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in cystic fibrosis: improved clinical outcomes but infection and inflammation persist
Authors: Michael M. Tunney, Peter Wark
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>Long-term therapy with elexacaftor/tezacaftor/ivacaftor (ETI) in cystic fibrosis results in improved clinical outcomes, but infection and inflammation persist</b>https://bit.ly/3PRaRwZ
Cover Image, Volume 43, Issue 6
Authors: Zhimin Ma, Jun Lv, Meng Zhu, Canqing Yu, Hongxia Ma, Guangfu Jin, Yu Guo, Zheng Bian, Ling Yang, Yiping Chen, Zhengming Chen, Zhibin Hu, Liming Li, Hongbing Shen
Journal: Cancer Communications (2023)

The cover image is based on the Original Article Lung cancer risk score for ever and never smokers in China by Zhimin Ma et al., https://doi.org/10.1002/cac2.12463.
Epigenetic reprogramming during the maternal‐to‐zygotic transition
Authors: Yurong Chen, Luyao Wang, Fucheng Guo, Xiangpeng Dai, Xiaoling Zhang
Journal: MedComm (2023)

Abstract After fertilization, sperm and oocyte fused and gave rise to a zygote which is the beginning of a new life. Then the embryonic development is monitored and regulated precisely from the transition of oocyte to the embryo at the early stage of embryogenesis, and this process is termed maternal‐to‐zygotic transition (MZT). MZT involves two major events that are maternal components degradation and zygotic genome activation. The epigenetic reprogramming plays crucial roles in regulating the process of MZT and supervising the normal development of early development of embryos. In recent years, benefited from the rapid development of low‐input epigenome profiling technologies, new epigenetic modifications are found to be reprogrammed dramatically and may play different roles during MZT whose dysregulation will cause an abnormal development of embryos even abortion at various stages. In this review, we summarized and discussed the important novel findings on epigenetic reprogramming and the underlying molecular mechanisms regulating MZT in mammalian embryos. Our work provided comprehensive and detailed references for the in deep understanding of epigenetic regulatory network in this key biological process and also shed light on the critical roles for epigenetic reprogramming on embryonic failure during artificial reproductive technology and nature fertilization.
The recent progress of myeloid‐derived suppressor cell and its targeted therapies in cancers
Authors: Ruiyang Ren, Chenyi Xiong, Runyu Ma, Yixuan Wang, Tianyang Yue, Jiayun Yu, Bin Shao
Journal: MedComm (2023)

Myeloid-derived suppressor cells (MDSCs) are an immature group of myeloid-derived cells generated from myeloid cell precursors in the bone marrow. MDSCs appear almost exclusively in pathological conditions, such as tumor progression and various inflammatory diseases. The leading function of MDSCs is their immunosuppressive ability, which plays a crucial role in tumor progression and metastasis through their immunosuppressive effects. Since MDSCs have specific molecular features, and only a tiny amount exists in physiological conditions, MDSC-targeted therapy has become a promising research direction for tumor treatment with minimal side effects. In this review, we briefly introduce the classification, generation and maturation process, and features of MDSCs, and detail their functions under various circumstances. The present review specifically demonstrates the environmental specificity of MDSCs, highlighting the differences between MDSCs from cancer and healthy individuals, as well as tumor-infiltrating MDSCs and circulating MDSCs. Then, we further describe recent advances in MDSC-targeted therapies. The existing and potential targeted drugs are divided into three categories, monoclonal antibodies, small-molecular inhibitors, and peptides. Their targeting mechanisms and characteristics have been summarized respectively. We believe that a comprehensive in-depth understanding of MDSC-targeted therapy could provide more possibilities for the treatment of cancer.
Blunted adaptive immune responses and acute exacerbations of COPD: breaking the code
Authors: Ken R. Bracke, Francesca Polverino
Journal: European Respiratory Journal (2023)

<h3>Tweetable abstract</h3> <b>J. Chen and co-workers provide mechanistic insight into the impaired antiviral CD8<sup>+</sup> T-cell immune responses upon cigarette smoke exposure</b> https://bit.ly/3CY7Bbb
Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD
Authors: Jana H. Badrani, Kellen Cavagnero, Jacqueline J. Eastman, Alex S. Kim, Allyssa Strohm, Carol Yan, Adam Deconde, Bruce L. Zuraw, Andrew A. White, Sandra C. Christiansen, Taylor A. Doherty
Journal: Journal of Allergy and Clinical Immunology (2023)

Aspirin-exacerbated respiratory disease (AERD) is associated with high levels of cysteinyl leukotrienes, prostaglandin D
BEDwARS: a robust Bayesian approach to bulk gene expression deconvolution with noisy reference signatures
Authors: Saba Ghaffari, Kelly J. Bouchonville, Ehsan Saleh, Remington E. Schmidt, Steven M. Offer, Saurabh Sinha
Journal: Genome biology (2023)

Differential gene expression in bulk transcriptomics data can reflect change of transcript abundance within a cell type and/or change in the proportions of cell types. Expression deconvolution methods can help differentiate these scenarios. BEDwARS is a Bayesian deconvolution method designed to address differences between reference signatures of cell types and corresponding true signatures underlying bulk transcriptomic profiles. BEDwARS is more robust to noisy reference signatures and outperforms leading in-class methods for estimating cell type proportions and signatures. Application of BEDwARS to dihydropyridine dehydrogenase deficiency identified the possible involvement of ciliopathy and impaired translational control in the etiology of the disorder.
CD20 × CD3 bispecific antibodies for lymphoma therapy: latest updates from ASCO 2023 annual meeting
Authors: Xinyuan Liu, Juanjuan Zhao, Xiangqian Guo, Yongping Song
Journal: Journal of Hematology & Oncology (2023)

Abstract Multiple bispecific antibodies (bsAbs) have been approved for cancer immunotherapy. Several CD20 × CD3 bsAbs have demonstrated significant anti-B-cell non-Hodgkin lymphoma (NHL) activity by engaging T cells to target CD20 + NHL cells in clinical trials. Mosunetuzumab, epcoritamab and glofitamab have been approved recently for B-cell NHL therapy. In this study, we summarized several latest reports on CD20 × CD3 bsAbs for the therapy of B-cell NHL from the ASCO 2023 annual meeting (ASCO2023).
Artificial cells delivering itaconic acid induce anti-inflammatory memory-like macrophages to reverse acute liver failure and prevent reinjury
Authors: Na Yin, Wenjun Zhang, Xiao-Xin Sun, Runxiu Wei, Qiang Yang, Fengming He, Changrui Li, Ling Guo, Min Feng
Journal: Cell Reports Medicine (2023)

Hepatic macrophages represent a key cellular component of the liver and are essential for the progression of acute liver failure (ALF). We construct artificial apoptotic cells loaded with itaconic acid (AI-Cells), wherein the compositions of the synthetic plasma membrane and surface topology are rationally engineered. AI-Cells are predominantly localized to the liver and further transport to hepatic macrophages. Intravenous administration of AI-Cells modulates macrophage inflammation to protect the liver from acetaminophen-induced ALF. Mechanistically, AI-Cells act on caspase-1 to suppress NLRP3 inflammasome-mediated cleavage of pro-IL-1β into its active form in macrophages. Notably, AI-Cells specifically induce anti-inflammatory memory-like hepatic macrophages in ALF mice, which prevent constitutive overproduction of IL-1β when liver reinjury occurs. In light of AI-Cells' precise delivery and training of memory-like hepatic macrophages, they offer promising therapeutic potential in reversing ALF by finely controlling inflammatory responses and orchestrating liver homeostasis, which potentially affect the treatment of various types of liver failure.